血清miRNA-21与糖尿病肾病不同分期中医证型及实验室指标的相关性研究
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摘要
目的观察血清miRNA-21与糖尿病肾病(diabetic nephropathy,DN)不同分期中医证型及实验室指标的相关性。方法将符合纳入标准的2型糖尿病(type 2 diabetes mellitus,T2DM)及DN患者60例分为T2DM、DNⅢ期、DNⅣ期、DNⅤ期共4组,每组15人,同时设立健康对照组15人,收集各组四诊资料,进行中医辨证分型;并检测各组血清miRNA-21表达水平及血肌酐(Scr)、尿素氮(BUN)、胱抑素C(CysC)、血清白蛋白(Alb)、胆固醇(CHOL)、甘油三酯(TG)、肾小球滤过率估计值(eGFR)、尿蛋白定量、血液流变学等指标。结果 DNⅤ期、DNⅣ期、DNⅢ期血清miRNA-21明显高于健康组(P<0.05);DNⅣ期较DNⅢ期增高(P<0.05);T2DM组与健康组无显著性差异(P>0.05),DNⅤ期较DNⅣ期明显下降(P<0.05)。中医辨证方面,阴虚燥热证比例最低,气阴两虚证次之(P<0.05);脾肾气虚证及阴阳两虚证比例最高(P<0.05);脾肾气虚证与阴阳两虚证无显著性差异(P>0.05)。血清miRNA-21表达情况,气阴两虚、脾肾气虚及阴阳两虚组均明显升高(P<0.05);其中脾肾气虚组与阴阳两虚组升高更明显(P<0.05);但脾肾气虚组与阴阳两虚组比较差异无统计学意义(P>0.05)。标证中,湿证者为16例,占26.7%,痰证15例,占25%,瘀证为29例,占48.3%,瘀证所占比例最高(P<0.05);瘀证组血清miRNA-21升高更明显(P<0.05);湿证组与痰证组比较,差异无统计学意义(P>0.05)。相关性研究结果显示,血清miRNA-21表达与DNⅢ期、DNⅣ期患者BUN、Cr、Cysc及血沉K值呈正直线相关,与eGFR呈显著负直线相关;对于DNⅤ期,血清miRNA-21仅与血沉K值呈显著正直线相关。结论血清miRNA-21在DN不同分期中表达差异明显,血清miRNA-21与DN患者某些实验室指标之间可能存在一定的相关性。
Objective To observe the correlation between serum miRNA-21 and diabetic nephropathy(DN)in different stages of TCM syndromes and laboratory indexes. Methods Sixty patients with type 2 diabetes mellitus(type 2 diabetes mellitusus,T2 DM)and DN were divided into 4 groups,15 in each group,and 15 healthy people in control group. Collect the data of four diagnoses in each group,and carry out TCM syndrome differentiation and typing. Serum miRNA-21 expression and serum creatinine(Scr),urea nitrogen(BUN),cystatin C(CysC),serum albumin(Alb),cholesterol(CHOL),triglyceride(TG),glomerular filtration rate estimated value(eGFR),urinary protein quantification and blood rheology were checked in each group. Results The level of serum miRNA-21 in DN V stage、DNⅣstage、DNⅢstage was significantly higher than that in normal group(P<0.05);DNⅣstage was higher than DNⅢstage(P<0.05);There was no significant difference between T2 DM group and normal group(P>0.05),The level of serum miRNA-21 in DN V stage was significantly lower than that in DN Ⅳ stage(P<0.05).In TCM syndrome differentiation,the proportion of yin deficiency and heat dryness syndrome was the lowest,qi and yin deficiency syndrome was the second(P<0.05),spleen and kidney qi deficiency syndrome and yin and yang deficiency syndrome was the highest(P<0.05),and there was no significant difference between spleen and kidney qi deficiency syndrome and yin and yang deficiency syndrome(P>0.05). The expression of serum miRNA-21 was significantly increased in the deficiency of Qi and Yin,deficiency of spleen and Kidney Qi and deficiency of Yin and Yang(P<0.05),especially in the deficiency of spleen and Kidney Qi and Yin and Yang groups(P<0.05),but there was no significant difference between the deficiency of spleen and Kidney Qi group and that of Yin and Yang deficiency group(P>0.05). There were 16 cases of dampness syndrome(26.7%),15 cases of phlegm syndrome(25%),29 cases of blood stasis syndrome(48.3%). The proportion of blood stasis syndrome was the highest(P<0.05),the serum miRNA-21 of blood stasis syndrome group was the highest(P<0.05);There was no significant difference between dampness syndrome group and phlegm syndrome group(P>0.05). The results of correlation study showed that the expression of serum miRNA-21 was positively correlated with BUN、Cr、Cysc and K value of erythrocyte sedimentation rate in patients with DN Ⅲ and DN Ⅳ,and negatively correlated with eGFR;while serum miRNA-21 was only positively correlated with K value of erythrocyte sedimentation rate in DN Ⅴstage. Conclusion The expression of serum miRNA-21 was significantly different in different stages of DN,and there might be some correlation between serum miRNA-21 and some laboratory indexes of DN patients.
Objective To observe the correlation between serum miRNA-21 and diabetic nephropathy(DN)in different stages of TCM syndromes and laboratory indexes. Methods Sixty patients with type 2 diabetes mellitus(type 2 diabetes mellitusus,T2 DM)and DN were divided into 4 groups,15 in each group,and 15 healthy people in control group. Collect the data of four diagnoses in each group,and carry out TCM syndrome differentiation and typing. Serum miRNA-21 expression and serum creatinine(Scr),urea nitrogen(BUN),cystatin C(CysC),serum albumin(Alb),cholesterol(CHOL),triglyceride(TG),glomerular filtration rate estimated value(eGFR),urinary protein quantification and blood rheology were checked in each group. Results The level of serum miRNA-21 in DN V stage、DNⅣstage、DNⅢstage was significantly higher than that in normal group(P<0.05);DNⅣstage was higher than DNⅢstage(P<0.05);There was no significant difference between T2 DM group and normal group(P>0.05),The level of serum miRNA-21 in DN V stage was significantly lower than that in DN Ⅳ stage(P<0.05).In TCM syndrome differentiation,the proportion of yin deficiency and heat dryness syndrome was the lowest,qi and yin deficiency syndrome was the second(P<0.05),spleen and kidney qi deficiency syndrome and yin and yang deficiency syndrome was the highest(P<0.05),and there was no significant difference between spleen and kidney qi deficiency syndrome and yin and yang deficiency syndrome(P>0.05). The expression of serum miRNA-21 was significantly increased in the deficiency of Qi and Yin,deficiency of spleen and Kidney Qi and deficiency of Yin and Yang(P<0.05),especially in the deficiency of spleen and Kidney Qi and Yin and Yang groups(P<0.05),but there was no significant difference between the deficiency of spleen and Kidney Qi group and that of Yin and Yang deficiency group(P>0.05). There were 16 cases of dampness syndrome(26.7%),15 cases of phlegm syndrome(25%),29 cases of blood stasis syndrome(48.3%). The proportion of blood stasis syndrome was the highest(P<0.05),the serum miRNA-21 of blood stasis syndrome group was the highest(P<0.05);There was no significant difference between dampness syndrome group and phlegm syndrome group(P>0.05). The results of correlation study showed that the expression of serum miRNA-21 was positively correlated with BUN、Cr、Cysc and K value of erythrocyte sedimentation rate in patients with DN Ⅲ and DN Ⅳ,and negatively correlated with eGFR;while serum miRNA-21 was only positively correlated with K value of erythrocyte sedimentation rate in DN Ⅴstage. Conclusion The expression of serum miRNA-21 was significantly different in different stages of DN,and there might be some correlation between serum miRNA-21 and some laboratory indexes of DN patients.
引文
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[15]杨婵娟,刘宏伟,王丽春,等.慢性乙型肝炎肝郁脾虚证和脾胃湿热证患者的差异表达基因研究初探[J].中国中西医结合杂志,2012,32(8):1032-1037.
[16]ZHANG Z,PENG H,CHEN J,et al.MicroRNA-21protects from mesangial cell proliferation induced by diabetic nephrology in db/db mice[J].FEBS Lett,2009,583(12):2009-2014.
[17]WANG J,GAO J,MA M,et al.Effect of miR-21 on renal fibrosis by regulating MMP-9 and TIMP1 in kk-ay diabetic nephropathy mice[J].Cell Biochem Biophys,2013,67(2):537-546.
[18]DEY N,DAS F,MARIAPPAN M M,et al.MicroRNA-21 orchestrates high glucose-induced signals to TORcomplex 1,resulting inrenal cell pathology in diabetes[J].J Biol Chem,2011,286(29):25586-25603.
[19]ZHONG X,CHUNG A C,CHEN H Y,et al.Smad3-mediated upregulation of miR-21 promotes renal fibrosis[J].J Am Soc Nephrol,2011,22(9):1668-1681.
[20]ZHONG X,CHUNG A C,CHEN H Y,et al.miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes[J].Diabetologia,2013,56(3):663-674.
[21]ZARJOU A,YANG S,ABRAHAM E,et al.Identification of a miRNA signature in renal fibrosis:role of miR-21[J].Am J Physiol Renal Physiol,2011,301(4):F793-F801.
[2]OGURTSOVA K,DA ROCHA FERNANDES J D,HUANG Y,et al.IDF Diabetes Atlas:Global estimates for the prevalence of diabetes for 2015 and 2040[J].Diabetes Research and Clinical Practice,2017,128:40-50.
[3]LIU Z H.Nephrology in China[J].Nature Reviews Nephrology,2013,9(9):523-528.
[4]VAN ROOIJ E.The art of microRNA research[J].CircRes,2011,108:219-234.
[5]WORLD HEALTH ORGANIZATIOn.Use of glycated hemoglobin(HbA1c)in the diagnosis of diabetes mellitus:abbreviated report of a WHO consultation[S].Geneva,WHO,2011:1-25.
[6]董雪娥,李会芳.Gas6与2型糖尿病及其并发症的研究进展[J].昆明医科大学学报,2018(3):119-124.
[7]MOGENSEN C E,SCHMITZ O.The diabetic kidney:from hyperfiltration and microalbum inuria to endstage renal failure[J].Medical Clinics of North America,1988,72(6):1465-1492.
[8]郑筱萸.中药新药临床研究指导原则(试行)[M].北京:中国医药科技出版社,2002:156-162.
[9]中华中医药学会肾病分会.糖尿病肾病诊断、辨证分型及疗效评定标准(试行方案)[J].上海中医药杂志,2007,41(7):7-8.
[10]ZHANG L,LONG J,JIANG W,et al.Trends in Chronic Kidney Disease in China[J].NEJM,2016,375(9):905-906.
[11]冯知涛,李娟,任洁.类风湿关节炎患者外周血miR-146a、miR-16的表达水平及临床指标与中医证型的关系探讨[J].热带医学杂志,2011,11(11):1226-1129.
[12]WANG J,GAO Y,MA M,et al.Effect of miR-21 on renal fibrosis by regulating MMP-9 and TIMP1 in KK-ay diabetic nephropathy mice[J].Cell Biochem Biophys,2013,67(2):537-546.
[13]秦玉花.Ⅱ型糖尿病肾虚证分布及基因表达谱研究[D].成都:成都中医药大学,2012.
[14]熊益群,姚小萍,周大桥,等.慢性乙型肝炎湿热中阻证与它证生物信息学差异研究[J].新中医,2012,44(4):32-34.
[15]杨婵娟,刘宏伟,王丽春,等.慢性乙型肝炎肝郁脾虚证和脾胃湿热证患者的差异表达基因研究初探[J].中国中西医结合杂志,2012,32(8):1032-1037.
[16]ZHANG Z,PENG H,CHEN J,et al.MicroRNA-21protects from mesangial cell proliferation induced by diabetic nephrology in db/db mice[J].FEBS Lett,2009,583(12):2009-2014.
[17]WANG J,GAO J,MA M,et al.Effect of miR-21 on renal fibrosis by regulating MMP-9 and TIMP1 in kk-ay diabetic nephropathy mice[J].Cell Biochem Biophys,2013,67(2):537-546.
[18]DEY N,DAS F,MARIAPPAN M M,et al.MicroRNA-21 orchestrates high glucose-induced signals to TORcomplex 1,resulting inrenal cell pathology in diabetes[J].J Biol Chem,2011,286(29):25586-25603.
[19]ZHONG X,CHUNG A C,CHEN H Y,et al.Smad3-mediated upregulation of miR-21 promotes renal fibrosis[J].J Am Soc Nephrol,2011,22(9):1668-1681.
[20]ZHONG X,CHUNG A C,CHEN H Y,et al.miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes[J].Diabetologia,2013,56(3):663-674.
[21]ZARJOU A,YANG S,ABRAHAM E,et al.Identification of a miRNA signature in renal fibrosis:role of miR-21[J].Am J Physiol Renal Physiol,2011,301(4):F793-F801.